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| Title | Binding mechanism and antagonism of the vesicular acetylcholine transporter VAChT. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 32, Issue 5, Page 818-827, Year 2025 |
| Publish date | Jan 13, 2025 |
Authors | Qiao Ma / Kunpeng Ma / Yanli Dong / Yufei Meng / Jun Zhao / Renjie Li / Qinru Bai / Di Wu / Daohua Jiang / Jianyuan Sun / Yan Zhao / ![]() |
| PubMed Abstract | The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. ...The vesicular acetylcholine transporter (VAChT) has a pivotal role in packaging and transporting acetylcholine for exocytotic release, serving as a vital component of cholinergic neurotransmission. Dysregulation of its function can result in neurological disorders. It also serves as a target for developing radiotracers to quantify cholinergic neuron deficits in neurodegenerative conditions. Here we unveil the cryo-electron microscopy structures of human VAChT in its apo state, the substrate acetylcholine-bound state and the inhibitor vesamicol-bound state. These structures assume a lumen-facing conformation, offering a clear depiction of architecture of VAChT. The acetylcholine-bound structure provides a detailed understanding of how VAChT recognizes its substrate, shedding light on the coupling mechanism of protonation and substrate binding. Meanwhile, the vesamicol-bound structure reveals the binding mode of vesamicol to VAChT, laying the structural foundation for the design of the next generation of radioligands targeting VAChT. |
External links | Nat Struct Mol Biol / PubMed:39806024 |
| Methods | EM (single particle) |
| Resolution | 2.7 - 3.4 Å |
| Structure data | EMDB-38651, PDB-8xtw: EMDB-38652, PDB-8xtx: EMDB-38653, PDB-8xty: |
| Chemicals | ![]() ChemComp-ACH: ![]() PDB-1lwl: |
| Source |
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Keywords | TRANSPORT PROTEIN / Transporter / Membrane protein / TRANSPORT PROTEIN/INHIBITOR / TRANSPORT PROTEIN-INHIBITOR complex |
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homo sapiens (human)
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